Differential assembly diversifies GABAA receptor structures and signalling

Andrija Sente (), Rooma Desai, Katerina Naydenova, Tomas Malinauskas, Youssef Jounaidi, Jonas Miehling, Xiaojuan Zhou, Simonas Masiulis, Steven W. Hardwick, Dimitri Y. Chirgadze, Keith W. Miller () and A. Radu Aricescu ()
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Andrija Sente: MRC Laboratory of Molecular Biology
Rooma Desai: Massachusetts General Hospital, Harvard Medical School
Katerina Naydenova: MRC Laboratory of Molecular Biology
Tomas Malinauskas: University of Oxford
Youssef Jounaidi: Massachusetts General Hospital, Harvard Medical School
Jonas Miehling: MRC Laboratory of Molecular Biology
Xiaojuan Zhou: Massachusetts General Hospital, Harvard Medical School
Simonas Masiulis: MRC Laboratory of Molecular Biology
Steven W. Hardwick: University of Cambridge
Dimitri Y. Chirgadze: University of Cambridge
Keith W. Miller: Massachusetts General Hospital, Harvard Medical School
A. Radu Aricescu: MRC Laboratory of Molecular Biology

Nature, 2022, vol. 604, issue 7904, 190-194

Abstract: Abstract Type A γ-aminobutyric acid receptors (GABAARs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits1,2 and can be modulated by essential medicines including general anaesthetics and benzodiazepines3. Human GABAAR subunits are encoded by 19 paralogous genes that can, in theory, give rise to 495,235 receptor types. However, the principles that govern the formation of pentamers, the permutational landscape of receptors that may emerge from a subunit set and the effect that this has on GABAergic signalling remain largely unknown. Here we use cryogenic electron microscopy to determine the structures of extrasynaptic GABAARs assembled from α4, β3 and δ subunits, and their counterparts incorporating γ2 instead of δ subunits. In each case, we identified two receptor subtypes with distinct stoichiometries and arrangements, all four differing from those previously observed for synaptic, α1-containing receptors4–7. This, in turn, affects receptor responses to physiological and synthetic modulators by creating or eliminating ligand-binding sites at subunit interfaces. We provide structural and functional evidence that selected GABAAR arrangements can act as coincidence detectors, simultaneously responding to two neurotransmitters: GABA and histamine. Using assembly simulations and single-cell RNA sequencing data8,9, we calculated the upper bounds for receptor diversity in recombinant systems and in vivo. We propose that differential assembly is a pervasive mechanism for regulating the physiology and pharmacology of GABAARs.

Date: 2022
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DOI: 10.1038/s41586-022-04517-3

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